The PTN Long-term Antipsychotic Pediatric Safety (LAPS) Trial, which aims to assess the long-term health risks of risperidone and aripiprazole in children, has now enrolled more than 100 children. Risperidone and aripiprazole have been shown to be effective for the treatment of conditions such as schizophrenia and bipolar disorder in adults, but little is known about the long-term health risks and quality-of-life benefits for their use in children.
While several antipsychotics are FDA-approved in children, it is common for these drugs to be prescribed without FDA approval for conditions such as attention-deficit disorder, obsessive-compulsive disorder, and major depression.
The ultimate goal of the study is to provide long-term safety data to the FDA to update the risperidone and aripiprazole labels to include correct safety and dosing information. This information will allow doctors to provide the safest, most effective dose to children who require treatment with antipsychotics.
The enrollment of more than 100 children helps achieve nearly 30 percent of the overall enrollment goal of the LAPS Trial and is a key accomplishment for the two-year observational study.
The Summer Training in Academic Research (STAR) Program welcomed 25 participants at its kickoff event Monday, June 17, at the Duke Clinical Research Institute (DCRI) in Durham, N.C. Now in its seventh year, the program provides hands-on research experience for undergraduate students, high school students, and middle and high school teachers during the summer academic break.
“The purpose of the program is to make sure we’re giving these students the opportunity to learn each day about various aspects of clinical research,” said Dr. Kanecia Zimmerman, leader of the program and associate professor of pediatrics at Duke University Medical Center. “The students may have never thought seriously about a career in medical research, and they come away thinking, ‘This is actually something I can do.’”
During the eight-week program, participants are placed in teams and matched with faculty mentors to work on original, hypothesis-driven projects. Participants also receive intensive instruction in developing scientific manuscripts, applied statistics, and data analysis.
A goal of the program is to have every trainee qualify for co-authorship on a peer-reviewed manuscript related to their team’s project. The research completed by the students will actually be used to further pediatric studies being conducted for the National Institutes of Health (NIH).
Nicholas Paredes, STAR program participant and rising high school sophomore from Sarasota, Fla., plans to earn a doctorate in biochemistry and biological engineering so he can focus his career on the testing of different medical treatments.
“I am particularly interested in conducting medical research and collaborating with others, knowing that the results would be used to improve existing technology,” he said. “Through the STAR program and the mentorship that is offered to its participants, I expect to work with renowned mentors and cooperate with my fellow members in a research team to write an academic paper that will successfully demonstrate the findings of our investigations.”
In addition to the research project, program participants attend lectures on neonatology, antimicrobial therapy, pharmacoepidemiology, and medical ethics. Eligible students also experience clinical medicine firsthand by shadowing a physician on hospital rounds.
The Pediatric Trials Network (PTN) recently published research in Antimicrobial Agents and Chemotherapy that tested the safety of intravenous rifampin for both premature and term infants. Rifampin is used to treat many different infections, including those caused by methicillin-resistant staphylococcus bacteria and tuberculosis. The newly published study shares findings from a study led by PTN investigator Dr. P. Brian Smith of the Duke Department of Pediatrics.
The study, which enrolled 27 infants total, analyzed plasma pharmacokinetic samples and safety data to determine the appropriate dosing of rifampin for infants. No adverse effects related to rifampin were seen, and drug clearance increased as weight and maturation increased.
Results showed that, for infants less than 14 days old, 8 milligrams of rifampin per kilogram of weight resulted in comparable exposure to adults receiving rifampin as a therapy against staphylococci infections and tuberculosis. In infants 14 days old or older, 15 milligrams per kilogram of weight showed similar results.
Representatives from the International Children’s Advisory Network (iCAN), a worldwide consortium of children’s advisory groups that provide a voice for children and families in medicine and research, shared their insights at a recent PTN symposium held Sunday, April 28, at the annual Pediatric Academic Societies (PAS) Meeting in Baltimore, Md.
Reece Ohmer, a high school senior who is preparing to go to college in the fall, has lived with type 1 diabetes since she was 8 years old. She discussed the experience of “turning a negative into a positive” by using her voice to advocate for better research for young people.
She joined iCAN when she was 12, after an especially taxing doctor’s appointment. She had received upsetting lab results, but no one had engaged her in the conversation.
“The doctor was talking to my mom and my mom was talking to my doctor, and I pretended I wasn’t listening,” she said. “But I was.”
After the appointment, she tearfully shared her frustrations with her mother, who responded by asking her what she would do to make that experience better for another child. Reece eventually joined the hospital’s teen advisory council, which in 2014 became one of seven hospitals participating in iCAN.
Through the consortium, she has worked to advocate for better funding for pediatric research, ensure access for more children, provide input on assent and consent forms to make them more understandable, and verify that available research is actually the research children need.
“We’ve helped increase understanding within the medical community that in patient-centered care, even the youngest voice matters,” Reece said.
iCAN representatives acknowledged that there is an element of distrust when researchers approach patients and families. Patients are often unsure where the researchers are coming from and whether they have their best interest at heart.
“They don’t know me and my life,” said Sophia Klaudt, an iCAN member and high school junior living with cystic fibrosis. “It’s hard to build that relationship with researchers when I’m just a case study to them.”
The iCAN representatives suggested that researchers may not be the best people to make the initial contact about research opportunities. “Have existing families who have already been through this experience help bridge that gap for you,” said Amy Ohmer, Reece’s mother and director of iCAN. “These patient ambassadors can share that empathy because they understand what it’s like to be in their shoes.”
When researchers need to approach patients directly, iCAN representatives suggested that a nurse or someone in a trusted position introduce them as a new member of the team who is coming from a genuine place of care and concern.
The iCAN representatives acknowledged the challenges of getting adolescents, who enjoy more freedom and are less bound by their parents’ demands, to adhere to their medications.
To better incentivize patients, Reece encouraged clinicians to get to know them and where they are in their care journey. Treating a 7-year-old is completely different than treating a 17-year-old, she said, and each group has its own motives.
“When I was seven, candy would have motivated me, or a chart on my refrigerator,” she said. “Now things that would incentivize me would be being able to do things on my own independently of my family, which is something I had to work for.”
Sophia stressed the importance of compromise, and trusting adolescents to make responsible decisions. “Ultimately, I know it’s my health,” she said.
Amy Ohmer added that, as a parent, it is critical to stop scolding and start empathizing.
“We don’t say enough to our young people that what they’re doing is tough,” she said. “We need to remind them of what’s happening that’s positive in their life.”
Communicating with patients
Asked how researchers can better communicate with young patients, Sophia recommended that they tailor communications to the patient’s age and maturity level, and that they ensure the patient is informed throughout the process.
“I’ve been in studies where I felt informed at the beginning, but I wasn’t informed throughout,” she said. “[Patients] need to understand what’s going on throughout the whole process and be informed of the results.”
iCAN representatives reminded researchers to keep the patient first in mind when developing materials. They recommended putting the most important information front and center, providing clear timelines so patients get a better sense of the level of commitment involved, and thanking participants and informing them of the impact they have had. Finally, they encouraged the use of newer technologies to communicate with young people, meeting them where they are.
“We are the future, and we are going to be the biggest return on your clinical research investment,” Reece concluded.
The Pediatric Trials Network (PTN) will host an informational symposium on Sunday, April 28, from 7:30 – 11:00 p.m. at the annual Pediatric Academic Societies (PAS) Meeting in Baltimore, Md. Register today to learn about the PTN’s contributions to child health and its unique perspectives as a network of more than 100 pediatric clinical research sites across the globe.
The symposium will begin with a brief overview of the PTN and the Best Pharmaceuticals for Children Act (BPCA), which aims to encourage the pharmaceutical industry to perform pediatric studies to improve labeling for medical products used in children. Perdita Taylor-Zapata, Pediatric Medical Officer at the NICHD, and Kanecia Zimmerman, Assistant Professor of Pediatrics at the Duke University School of Medicine, will provide opening remarks.
Three presentations will follow:
Matthew Laughon of the University of North Carolina at Chapel Hill and Kelly Wade of the Children’s Hospital of Philadelphia will provide real-world applications of PTN’s work and discuss the impact of clinical research in practice.
Parents and adolescent participants in the International Children’s Advisory Network (iCAN) will participate in a panel discussion on how researchers can better engage with participants and caregivers.
Janice Sullivan of the University of Louisville will spotlight partnering opportunities and work being done within and across research networks.
The symposium will conclude with a discussion of future opportunities for the PTN and pediatric research by Perdita Taylor-Zapata.
The Pediatric Trials Network (PTN) recently published research in the Journal of the American Academy of Dermatology (JAAD) that explores whether topicalA timolol used on infants is absorbed through the skin and can be detected in the blood. The newly published research shares findings from a study led by Drs. Beth Ann Drolet and Kristen Holland of the Medical College of Wisconsin in Milwaukee. In this study, 76 children less than two years of age receiving timolol, as prescribed by their doctor, were monitored for a 90-day period and blood samples were collected.
Timolol is a beta blockerB that has increasingly been used for the treatment of Infantile Hemangiomas (IH), also commonly called “strawberry” birthmarks, on infants’ skin. However, little is known regarding the safety of topical timolol’s use.
In the PTN study, 75 children received a 0.5% concentration of timolol and one child received 0.25%. While it was predicted that young infants would have higher concentrations of timolol in their blood, the study found that older infants and those with thicker hemangiomas had the highest concentrations. There were no reports of serious unexpected adverse events during the 90-day study period.
An additional Phase IIC trial will aid in determining the best and most effective dose of timolol in infants. However, the published research indicates that two drops of 0.5% timolol per day should not be exceeded in the treatment of small, thin hemangiomas. For the treatment of thicker hemangiomas, oral medicationD is recommended.
Research conducted by the Pediatric Trials Network (PTN) has led the U.S. Food and Drug Administration (FDA) to update the prescribing information, or drug label, of acyclovir to include dosing for infants with Neonatal Herpes Simplex Virus (HSV) based upon the infants post-menstrual age. Acyclovir (brand name Zovirax) is an antiviral drug used in the pediatric population to treat HSV, a highly contagious virus that can be very serious for babies.
Because an infant’s immune system is not fully developed to fight off the virus, the disease can result in death or mental disabilities. While appropriate dosing of acyclovir was known for adults and children, acyclovir had not been adequately studied in full-term or preterm infants.
In the two associated PTN studies, 32 infants were enrolled. The first study was conducted at a single medical center in preterm and term infants with suspected HSV infection. The second study involved multiple medical centers and enrolled only preterm infants with suspected HSV infection.
Based upon the pharmacokinetic (how a drug travels through the body) results, the FDA updated the label to include dosing in infants based on their post-menstrual age (PMA), or the time that had elapsed since the mother’s last menstrual cycle. PMA is especially useful in preterm infants because it characterizes the baby’s expected developmental age.
With a nearly 30-year history in academic research, Dr. Christine Turley offers a variety of perspectives into the world of clinical research. After a start in private practice, Dr. Turley went on to spend a large portion of her career in vaccine research and development. A general pediatrician by trade, Dr. Turley currently serves as director of the Research Center for Transforming Health at the University of South Carolina. The mission of the center is to help investigators and their teams conduct transformative research by helping overcome barriers that are often present in newer research settings.
Prior to her current position, Dr. Turley served in a variety of roles at the University of Texas Medical Branch (UTMB) in Galveston, Tex. She worked in clinical education, was the vice chair of Clinical Programs, and was heavily involved in the institution’s clinical operations.
She is currently involved in the administration of the Pharmacokinetics of Understudied Drugs Administered to Children per Standard of Care (PTN POPS) study at the University of South Carolina. We recently spent time discussing the importance of the study as well as clinical research in general.
Q: How would you explain the importance of clinical research, specifically for children?
A: We treat children every day and we try to treat them with the best evidence possible. But what we’re realizing is that, in many cases, the evidence is limited. In many cases we’re treating based on experience instead of data. The other thing about research, specifically in children, that is really important is that many chronic diseases originate in childhood. Our opportunity to help prevent this trajectory has never been more compelling than it is now. It’s too late to start working on hypertension when people are 50. We’re realizing now that it’s better to start at the very beginning of a person’s life.
Q: Why should people care about the findings of the PTN POPS study?
A: Over time, we’ve seen the level of variability that exists in children. The physiology of children changes very much over the child’s lifespan. It may seem obvious, but a 17 year old is very different than a seven month old. As we’re using medications on children, it’s important that we get better information so that we’re providing the best care possible and not running the risk of worsening conditions. We know we can do better, and studies like PTN POPS provide us with the opportunity to do better and provide better care for children.
A: ISPCTN is a component of the larger NIH Environmental Influences on Child Health Outcomes (ECHO) program. The IDeA State initiative weaves together the pediatric research community in a very interesting way by including other pediatric investigators and populations that are important, but otherwise may not have an opportunity to participate in ECHO. As a result, the research community becomes much more holistic and places an equal value on all components, creating synergy for pediatric research across the country. The capacity enhancements are wonderful and it’s very gratifying to invite other groups into research that may not have an opportunity otherwise.
Q: What are the benefits of having the University of South Carolina involved in the PTN POPS study?
A: There are three levels at which I see a benefit to USC’s involvement with PTN POPS. The most traditional is that we’ve been able to enroll patients in this study and engage with clinical investigators in other areas. At the bedside level, the teams are very interested in this project because they feel like there is the opportunity to impact patients they see every day. The second benefit is that it has proven the value of research to our group, which is relatively small and young in comparison to others. The third is that it has proven the value of research to our leadership. Even though we’re not enrolling 1,000 kids and making a huge amount of money for our institution, it is extremely relevant to the safety and quality of our care, which we all care about very much.
The American Academy of Pediatrics (AAP) posted an article on the AAP News website to spotlight the work done by the Pediatric Trials Network (PTN) to provide much-needed dosing, safety and efficacy information for off-patent drugs used in children. The article was written by Perdita Taylor-Zapata of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and P. Brian Smith of the PTN and the Duke Department of Pediatrics.
Despite pediatric medicine’s long history of catastrophic events resulting from inadequate study of drugs prior to their widespread use, the majority of drugs used in children have undergone insufficient study to receive pediatric-specific labeling from the FDA. To fill this troubling information gap, the NICHD established the PTN at the Duke Clinical Research Institute. The PTN generates data to help regulators update drug labels for safer and more effective use of medications in infants and children, in keeping with the goals of the Best Pharmaceuticals for Children Act (BPCA).
BPCA became law in 2002 and provides a mechanism to study off-patent drugs through a collaborative effort of the National Institutes of Health (NIH) and the FDA. This effort includes identifying drugs and therapeutic areas that lack pediatric dosing, safety or efficacy data; sponsoring clinical trials for prioritized drugs; and submitting study results to the FDA for consideration of label modification.
PTN trials are conducted across the U.S. and other countries in partnership with the NIH, and eight clinical trials are ongoing. More than 100 clinical sites are enrolling children in PTN trials, and more than 7,000 children have been enrolled to date.
The PTN has submitted data to the FDA for 21 drugs and devices. To date, eight label changes have been made based on clinical trials sponsored by the NIH BPCA program, including recent label changes to lisinopril and meropenem.
The American Academy of Pediatrics (AAP) has updated the 2018 edition of the Red Book to include fluconazole dosing information determined by a Pediatric Trials Network (PTN) study. The Red Book is the leading resource on pediatric infectious disease, providing the most up-to-date information on a wide variety of diseases that doctors see in children.
The updates include dosing information for the treatment of Cryptococcus neoformans and Cryptococcus gattii infections, as well as Cryptococcal meningitis in children. The updates, which can be viewed on Red Book Online, will enable doctors to provide a safer, more accurate dose of the antifungal drug fluconazole to treat these diseases in children.
The changes were based on a study conducted from 2008 to 2011 in collaboration with PTN that analyzed safety data on the use of fluconazole to treat infections caused by the Candida yeast. While Candida and Cryptococcus yeasts are not the same, they are treated similarly enough to allow dosing information for one to apply to the other. The study examined data from nearly 800 infants in three randomized trials.
The research was supported in part by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).